Effects of exercise during chemotherapy for breast cancer on long-term cardiovascular toxicity

Objective Animal data suggest that exercise during chemotherapy is cardioprotective, but clinical evidence to support this is limited. This study evaluated the effect of exercise during chemotherapy for breast cancer on long-term cardiovascular toxicity. Methods This is a follow-up study of two previously performed randomised trials in patients with breast cancer allocated to exercise during chemotherapy or non-exercise controls. Cardiac imaging parameters, including T1 mapping (native T1, extracellular volume fraction (ECV)), left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS), cardiorespiratory fitness, and physical activity levels, were acquired 8.5 years post-treatment. Results In total, 185 breast cancer survivors were included (mean age 58.9±7.8 years), of whom 99% and 18% were treated with anthracyclines and trastuzumab, respectively. ECV and Native T1 were 25.3%±2.5% and 1026±51 ms in the control group, and 24.6%±2.8% and 1007±44 ms in the exercise group, respectively. LVEF was borderline normal in both groups, with an LVEF<50% prevalence of 22.5% (n=40/178) in all participants. Compared with control, native T1 was statistically significantly lower in the exercise group (β=−20.16, 95% CI −35.35 to −4.97). We found no effect of exercise on ECV (β=−0.69, 95% CI −1.62 to 0.25), LVEF (β=−1.36, 95% CI −3.45 to 0.73) or GLS (β=0.31, 95% CI −0.76 to 1.37). Higher self-reported physical activity levels during chemotherapy were significantly associated with better native T1 and ECV. Conclusions In long-term breast cancer survivors, exercise and being more physically active during chemotherapy were associated with better structural but not functional cardiac parameters. The high prevalence of cardiac dysfunction calls for additional research on cardioprotective measures, including alternative exercise regimens. Trial registration number NTR7247.


Echocardiography
Transthoracic 2D-echocardiograms were acquired using a GE Vivid E9 or E95 machine.In line with current guidelines for adult cancer survivors [1], measurements of LV function, dimensions, and diastology were performed using one cardiac cycle.Diastolic function was scored as normal, indeterminate, or diastolic dysfunction, according to the most recent guidelines [2].Global longitudinal strain (GLS) was assessed via 2D-speckle tracking echocardiography in the apical four-, three -and two-chamber views using offline EchoPAC software (version 2.03, GE Vingmed, Horten, Norway).All echocardiography data were collected by the same researcher (WN), after receiving sufficient training in GLS analysis [3], and were reviewed by the same cardiologist (AT), blinded for original treatment allocation.

Cardiopulmonary exercise tests
Cardiorespiratory fitness was assessed with a cardiopulmonary exercise test with continuous breathing gas analysis.Cycling workload increased every minute by 10,15 or 20 W till exhaustion, on the basis of participants' symptoms or at the discretion of the supervising physician.Peak oxygen uptake (VO2Peak) was defined as the average value for the last 30 seconds before exhaustion and expressed in ml/kg/min.Only maximum exercise tests, defined as those where the respiratory exchange rate ≥1.1, were included in the analysis.

Venous blood sample
A fasting venous blood sample was taken to determine hematocrit (for ECV calculation), renal function, and presence of diabetes mellitus and hypercholesterolemia.

Physical activity
The original PACT and PACES study used different questionnaires to assess physical activity before diagnosis; the Short Questionnaire to Assess Health enhancing physical activity (SQUASH) [4] and the Physical Activity Scale for Elderly (PASE) [5], respectively.In the FU study, the former questionnaire was used.This questionnaire comprises questions on commuting activing, leisure-time and sports activities, household activities and work-related activities.We calculated the minutes per week of moderate-to high-intensity leisure and sport physical activity, which include all activities that correspond with a MET-value of ≥ 3.0.To obtain an estimate for physical activity participants engaged in over the past years (i.e.since completion of the original PACT and PACES studies), we used a structured, face-to-face interview [6].
All interviews were performed by the same researcher (WN).Total physical activity scores were derived in MET-hours per week [6].

Supplementary Table 1b. Characteristics at baseline of original PACES participants, and those of participants and non-participants of the
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Pact-Paces-Heart study.Presented as mean ± SD, median (interquartile range] or number (percentages).